The long term objectives of this project are to understand the immunological and genetic basis for susceptibility to tuberculosis. As the effectiveness of cellular immunity to Mycobacterium tuberculosis determines whether infection evolves into clinical disease, a better understanding of the immune response and the genes that govern it will facilitate a more rational approach to development and use of vaccines, drugs, and biological therapy. An aerosol route of inoculation will be used to infect intact mice that are either inherently resistant or susceptible to tuberculosis. The local immune response in the lung will be compared to the systemic response in the spleen using a variety of techniques including the quantitation of T cell subsets, intracellular cytokines staining, and RNAse protection assays in order to define immunological parameters that indicate a protective immune response. Other investigations will ascertain which genetic loci are critical for disease resistance. With this insight, these techniques will be applied to interventional models to determine how different treatment strategies modify the immune response during primary infection (in the case of vaccines and biological treatments) or after subsequent rechallenge (in the case of chemotherapy). Finally, two different models that approximate the cell mediated defects observed in HIV/AIDS will be examined to determine how the immune response is altered to M. tuberculosis infection in the absence of CD4 plus T cells, and whether therapeutic interventions can beneficially augment the innate and adaptive immune responses under these conditions. The specific aims are as follows: Aim 1. Characterize the immunological differences between mouse strains that are either resistant or susceptible to infection with Mycobacterium tuberculosis after aerosol inoculation. Aim 2. Determine the genetic derangements that correlate with susceptibility and resistance. Aim 3. Identify how the immune response to tuberculosis changes as a consequence of therapeutic interventions in an animal model. Aim 4. Characterize the immune response to tuberculosis in mouse models that simulate the abnormalities of cell mediated immunity typical of HIV/AIDS patients.